Rhabdomyolysis caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Rhabdomyolysis is a severe potential adverse drug reaction of statin therapy. We report a case of rhabdomyolysis due to drug-drug interaction (DDI) between atorvastatin and fluconazole and review the literature. CASE SUMMARY: A 70-year-old woman received atorvastatin for hyperlipidaemia without any problem for 4 years. When intravenous fluconazole was added for treating a fungal infection, rhabdomyolysis developed 2 weeks later. Removal of atorvastatin led to the resolution of her rhabdomyolysis. WHAT IS NEW AND CONCLUSION: Our case demonstrates that in some subjects even a moderate CYP3A4 inhibitor such as fluconazole may lead to rhabdomyolysis in subjects receiving a statin.

High risk of cross-reactivity between vancomycin and sequential teicoplanin therapy.

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin and vancomycin show similar clinical and bacteriological efficacy in clinical trials. Teicoplanin has been reported to have a lower adverse drug reaction (ADR) rate than vancomycin. Cross-reactivity between these two glycopeptides is controversial. Our aim was to study the cross-reactivity between teicoplanin and vancomycin through an assessment of all the reported ADRs of these drugs in our University hospital. METHODS: Over a period of 2 years, 170 cases of vancomycin therapy, which were closely monitored by doctors and clinical pharmacists, were used to analyse ADRs. Teicoplanin therapy was used as an alternative in cases of vancomycin intolerance. When an ADR related to vancomycin or teicoplanin was suspected, specialists were consulted to confirm if these were true ADR and to determine whether the implicated drug should be stopped. All ADRs for the two glycopeptides were assessed for causality using the Naranjo probability scale. RESULTS AND DISCUSSION: Thirty-eight of 170 patients (22·4%) treated with vancomycin developed ADRs. Twenty-four patients were switched to teicoplanin. However, 14 of those 24 patients (58·3%) developed ADRs. The time of onset of ADRs involving vancomycin was 12·7 ± 10·9 days (range, 1-46 days). The time of onset of sequential teicoplanin-induced ADRs was 11·7 ± 4·7 days (range, 2-20 days). Of the 14 patients with ADRs related to sequential teicoplanin therapy, six showed cross-reactivity between vancomycin and teicoplanin. The incidence of vancomycin-induced neutropenia was 4·7% (8/170), whereas the incidence of teicoplanin-induced neutropenia subsequent to vancomycin intolerance was as high as 33·3% (8/24). Furthermore, 71·4% (10/14) of the teicoplanin-induced ADRs were associated with haematological abnormalities such as neutropenia, thrombocytopenia or leucopenia. WHAT IS NEW AND CONCLUSION: Teicoplanin, used as an alternative in cases of vancomycin intolerance, was associated with a high incidence of ADRs and haematological reactions, most notably neutropenia. This high rate of ADRs suggests cross-reactivity between the two glycopeptides.

Teicoplanin-induced hypersensitivity syndrome with a preceding vancomycin-induced neutropenia: a case report and literature review.

Hypersensitivity syndrome associated with teicoplanin has rarely been reported. We report a case with a preceding episode of vancomyin-related neutropenia. A 47-year-old female with cervical spine infection was treated with vancomycin. Neutropenia occurred after 17 days of vancomycin therapy. Vancomycin was changed to teicoplanin, and the neutropenia resolved 4 days later. After 11 days of teicoplanin therapy, a new episode of hypersensitivity syndrome manifested as fever, bilateral neck lymphadenopathy, mild wheezing, hepatitis and increased CRP occurred. Neutropenia and thrombocytopenia developed 3 days later. The patient's symptoms settled over 1 week following withdrawal of teicoplanin. Naranjo's ADR algorithm categorized the neutropenia associated with vancomycin and the hypersensitivity syndrome associated with teicoplanin as 'probable'.

Differential response to H. pylori eradication therapy of co-existing diffuse large B-cell lymphoma and MALT lymphoma of stomach-significance of tumour cell clonality and BCL10 expression.

We recently reported that low-grade mucosa-associated lymphoid tissue lymphoma (MALToma) and diffuse large B-cell lymphoma (DLBCL) with MALToma (DLBCL[MALT]) of stomach are equally responsive to H. pylori eradication therapy (HPET) and that H. pylori-independent status is closely associated with nuclear translocation of BCL10. However, co-existing MALToma and DLBCL components of gastric DLBCL(MALT) may respond differentially to HPET and the underlying mechanism remains unclear. Tumour tissue samples from 18 patients with microdissectable co-existing MALToma and DLBCL cells were studied. The clonality of lymphoma cells was examined by polymerase chain reaction-based amplification of the CDR3 region of the IgH gene and confirmed by DNA sequence analysis. BCL10 expression was determined by immunohistochemistry. Differential response of co-existing MALToma and DLBCL to HPET was defined as complete eradication of one component while the other component remained. Five (27.8%) of the 18 patients showed different IgH gene rearrangements in the two components and three (60%) of these five patients had differential response of MALToma and DLBCL to HPET. By contrast, 13 patients showed identical IgH gene rearrangements and only one (8%) of them had differential response of the two components to HPET (p = 0.044). Further, all four patients with differential response of MALToma and DLBCL to HPET showed nuclear expression of BCL10 in the H. pylori-independent component and cytoplasmic expression of BCL10 in the H. pylori-dependent component while the expression patterns of BCL10 were identical in both of these components in the 14 patients who had similar tumour response to HPET. We conclude that different clonality is a common reason for the differential response of co-existing MALToma and DLBCL of gastric DLBCL(MALT) to HPET and that immunohistochemical examination of BCL10 expression may help to identify the co-existence of these components.

Nuclear extracellular signal-regulated kinase 2 phosphorylates p53 at Thr55 in response to doxorubicin.

In this study, we showed that nuclear ERK2 phosphorylates p53 at Thr55 in response to doxorubicin. p53 was found to physically interact with ERK2 as evidenced by Western blotting of ERK2 coimmunoprecipitated complex. The gene fragment encoded for N-terminal 68 amino acids was subcloned and fused with 6-His. Each serine or threonine site in this fragment, the possible phosphorylation site, was mutated to alanine. The recombinant proteins were used as substrates in ERK2 kinase assay. The results show that ERK2 phosphorylated p53 at Thr55. Further, electromobility shift assay showed that the phosphorylation of p53 by nuclear ERK2 was closely related to the transactivating activity of p53. These findings suggest that ERK2 may play a role in response to DNA damage via interaction with p53.

Size-dependent permeability of hydrophilic probes across rabbit colonic epithelium.

Colon-specific delivery of metabolically labile molecules, such as proteins and peptides, is of particular interest in pharmaceutical research. Among the factors that may influence the permeability of drug molecules across colonic mucosa are their molecular weight and geometry. The purpose of this study was to evaluate the influence of molecular geometry on in vitro permeability across rabbit distal colonic epithelia. Permeability of radiolabeled hydrophilic probes with different molecular weights and geometries across isolated rabbit distal colonic tissue was evaluated by means of the Ussing chamber technique. The hydrodynamic radii of the probes (an indicator of molecular geometry) were estimated by theoretical models as well as dynamic light scattering. We conducted the permeability studies in the presence and absence of the epithelial cells to evaluate the contribution of the underlying connective tissue to the overall in vitro permeability across the colonic mucosa. The rank order of the permeability of the markers was mannitol > lactulose > polyethylene glycol (PEG) 400 > PEG 900 > PEG 4000, which is consistent with their molecular weights and estimated hydrodynamic radii. The permeability of inulin, a polyfructose molecule with a molecular weight of about 5000, however, was approximately the same as that of PEG 900 (molecular weight about 900). When the epithelial cells were removed, for the homologous series of PEGs, the permeabilities were proportional to their free diffusion coefficients in water. It appears that for the PEG and lactulose probes, theoretical estimation of the hydrodynamic radii, which assumes the molecules to be spherical in shape, provides a good basis for the dependence of permeability on geometry. The relatively high permeability of inulin seems to be due to its compact structure. The PEG permeability values in the absence of epithelial cells, in combination with their diffusion coefficients, indicate that the underlying connective tissue does not contribute to the overall permeability of these molecules across colonic mucosa in vitro.

Effect of medium-chain glycerides on physiological properties of rabbit intestinal epithelium in vitro.

Medium chain glycerides (MCGs) have been reported to enhance intestinal absorption of hydrophilic drugs. However, the mechanisms involved in absorption enhancement are not well understood. The effects of MCGs (CapMul MCM) on physiological properties of rabbit ileum and distal colon, including active ion transport, transepithelial resistance (Rt) and passive permeability, have been investigated in vitro. CapMul MCM inhibited active ion transport (measured as a decrease in short-circuit current, Isc) in both intestinal segments in a concentration-dependent manner. The inhibition of Isc was rapidly reversible (within 100 min) upon removal of CapMul MCM. The data indicate that CapMul MCM preferentially affected ion transport by villus cells in the ileum and surface cells in the distal colon. Ion transport in crypt cells in both segments was not significantly altered. Rt of the ileum was not significantly affected by 5% CapMul MCM, while mannitol transport was 6 fold enhanced. Treatment of distal colon with 1% CapMul MCM reduced Rt by 95%, while mannitol transport was 100 fold enhanced. In a parallel experiment, mucosal(m)-to-serosal(s) transport of cephalexin, a beta-lactam antibiotic, in the ileum was about 40% reduced in the presence of 5% CapMul MCM, whereas transport in the s-to-m direction was 2.5 fold enhanced. Treatment of the distal colon with 1% CapMul MCM resulted in 25 fold enhancement of cephalexin transport in either direction. These results suggest that absorption enhancement by MCGs results from an increased permeability of the intestine confined to the villus or surface epithelium.

Adsorption of firefly luciferase at interfaces studied by total internal reflection fluorescence spectroscopy.

The adsorption of luciferase onto silica surfaces was studied by total internal reflection fluorescence (TIRF) spectroscopy. Two model surfaces were used: hydrophilic and hydrophobic silica. Luciferase adsorbed differently on these two surfaces. Initial kinetics of luciferase adsorption onto the hydrophilic surface showed that luciferase adsorbs over an adsorption energy barrier of ≈3 kT The quantum yield of luciferase fluorescence decreased at the hydrophilic silica surface, which indicated that the protein conformation was altered during adsorption. Luciferase adsorption onto the hydrophobic silica surface proceeded with a small adsorption energy barrier and the fluorescence efficiency of adsorbed protein remained unchanged after adsorption. The affinity of luciferase for luciferin was measured using quenching of luciferase fluorescence with luciferin. The binding constant of the adsorbed luciferase-luciferin complex at the hydrophilic silica surface was two orders of magnitude smaller than the respective binding constant in the solution. Adsorbed luciferase showed an absence of ATP-dependent visible luminescence, indicating that the adsorbed enzyme was not active at either of the two silica surfaces.